Oct. 20, 1955
NOTES
tion sequence may prove to be of interest for the synthesis of 2,5-diarylthiazoles ; the only previously recorded synthesis of 2,5-diphenylthiazole involved the reaction of benzaminoacetophenone with phosphorus pentasulfide.'
of aqueous ammonia (1: 1) was shaken for about five minutes and the yellow solid then collected by filtration, washed with water and dried; yield 3.74 g. (99%), m.p. 103.5104.5'. Anal. Calcd. for C1,H1tN& C, 71.1; H , 5.2; N, 11.1. Found: C, 71.3; H, 4.9; N, 10.9. 2,s-Diphenylthiazole .-One gram of 4-amino-2,5-diphenylthiazole was dissolved in a mixture of 30 ml. of ethanol and 15 ml. of concentrated hydrochloric acid. The solution was cooled to 0' and 4 ml. of a 20% solution of sodium nitrite added. After the mixture had stood for one hour, 0.1 g. of powdered copper was added and the solution was warmed to 50". It then was filtered and the filtrate evaporated to about 20 ml. and cooled. The crystals which separated were recrystallized twice from absolute ethanol to give 0.27 g. (29%) of 2,5-diphenylthiazole, m.p. 103104'. The reported melting point for 2,5-diphenyIthiazole is 103-104°.4 Anal. Calcd. for ClsH~lT\'S: C, 75.9; H , 4.7; N, 5.9. Found: C, 76.0; H , 4.5; X, 5.8. 2,5-Diphenyl-4(5)-thiazolone.-A mixture of 3.78 g. of 4-amino-2,5-diphenylthiazole and 80 ml. of 40% sulfuric acid was heated under reflux for ten hours. The yellow product started separating from the hydrolysis mixture after about one hour. The cooled mixture then was filtered and the collected solid washed well hith water and recrystallized from absolute ethanol toogive 3.62 g. (95%) of bright yellow crystals, m.p. 215-215.5 . A n d . Calcd. for Cl6HJ1ONS: C, 71.1; H, 4.4; K , 5.5. Found: C, 71.2; H , 4.6; N, 5.5. KOYESCHEMICAL LABORATORY OF ILLINOIS UNIVERSITY ILLISOIS URBANA,
CN
/
[
OSO:CF,H~ CBH~C /H
HS=C\
HY
1
ICCsH5 S
111
HS
ll
[
]
7s H i CBI-I,CH\~,CC~HS
I I1
I
J.
J.
1'
IV
544,j
The Synthesis of N-Methyl-3-cyano-4-methoxy-6I n contrast to the extreme lability of the majorpyridone, a Structural Isomer of Ricinine ity of previously prepared 4-aminothiazoles toward J R . , ~ALDOJ. CROVETTI AKD HARVEY M. acid hydrolysis,213,5-84-amino-2,5-diphenylthiazole BY E. e. TAYLOR, Loux (prepared from the benzenesulfonic acid salt by RECEIVED MAY31, 1955 treatment with ammonium hydroxide) proved to be remarkably stable and could be recovered unDuring the course of a program concerned with changed after treatment with boiling alcoholic hy- the chemistry of pyridine-N-oxides, which recently drochloric acid for ten minutes. It was converted has led to a new synthesis of the alkaloid ricinine in 95y0yield to 2,5-diphenyl-4(5)-thiazolone(V) by (I),z we had occasion to prepare for comparison purheating under reflux with 40% sulfuric acid for ten poses a hithertofore unknown structural isomer of hours. this alkaloid. The condensation of diethyl acetoneAttempts to condense I with thioacetamide and dicarboxylate with ethyl orthoformate and ammoa-phenylthioacetamide were unsuccessful, the only nia was carried out according to the method of den products isolated being ammonium chloride, am- Hertog3 to give ethyl 4,6-dihydroxynicotinate (II), monium benzenesulfonate and indefinite sulfur- which was converted to the corresponding amide I11 containing oils. with anhydrous ammonia in a sealed steel bomb a t Experimental 150'. Treatment of I11 with a mixture of phos4-Arnino-2,5-diphenylthiazoleBenzenesulf0nate.-A mix- phorus oxychloride and phosphorus pentachloride ture of 5.46 g. (0.02 mole) of a-cyanobenzyl benzenesulfo- effected chlorination and simultaneous dehydration nate and 2.76 g. (0.02 mole) of thiobenzamide in 50 ml. of to give 4,6-dichloronicotinonitrile (IV) in an overabsolute ethanol was warmed on a steam-bath for about one minute to effect solution and then allowed to stand a t 0" all yield of 67%, based on 11. An alternative and overnight. The yellow solid which had separated was col- lengthier route to IV has been described by den lected by filtration, washed with cold absolute ethanol and H e r t ~ g . ~ recrystallized three times from absolute ethanol to give Sodium methoxide in methanol converted IV in 3.02 g. (37%) of light yellow crystals, m.p. 198-199'. 94% yield to 4,6-dimethoxynicotinonitrile (V), Anal. Calcd. for Cl&&2S.C&03S: C, 61.4; H , 4.4; which was isomerized with methyl iodide in a sealed S , 6.8. Found: C, 61.7; H, 4.3; hT,6.9. 4-Amino-2,5-diphenylthiazole.-A mixture of 6.15 g. of tube in 93yo yield to N-methyl-3-cyano-4-meth4-amino-2,5-diphenylthiazolebenzenesulfonate and 50 ml. oxy-6-pyridone (VI), a structural isomer of ricinine. The structure of the product was confirmed by hy(4) H . Gabriel, Bcr., 43, 134 (1910). drolysis with concentrated hydrochloric acid to N(5) W. Davies, J. A. Maclaren and L. R . Wilkinaon. J.Chcm. Soc.. 3491 (1950). (6) R . M Dodson and H. W. Turner, THIS JOURNAL, 73, 4517 (1951). (7) W. Zerweck and M . Schubert, German Patent 729,853; Chcm. Z e n t v . , 114, I, 2035 (1943). ( 8 ) A. H. r a n d , C . Ziegler and J . hf.Sprague, J. Orf. C h r m . , 11, 617 (1946).
(1) Frick Chemical Laboratory, Princeton University, Princeton, N. J . (2) E. C. Taylor, J r . , and Aldo J. Crovetti, THISJOURNAL, 77, in press. (3) H. J. den Hertog, Rec. tuaw. chim., 6S, 129 (1946). (4) H. J . den Hertog, J. C. M . Schopt. J. de Bruyn and A. de Klerk ibid.. 69, 673 (1950).
inethyl-4-hydroxy-2-pyridone(VII), which also is formed by similar treatment of ricinine itself .5 It is of interest that the isomerization of IT to VI took place much more readily than the analogous isomerization of 2,4-dimethoxynicotinonitrile to ricinine.2sfi OCHi
OH
CH:r I
TI 0 €I
111 OCH3
I'
CI
I1' OCHi
I
CH3 vI
OH
I
CH? VI I
Experimental 4,6-Dihydroxynicotinamide @I).-A mixture of 10 g. of ethyl 4,6-dihydroxynicotinate3and 70 ml. of liquid ammonia was sealed in a steel bomb and heated a t 150' for a period of 3 hours (the internal pressure a t this temperature is 1900 lb./sq. in.). Removal of excess ammonia gave 8.4 g. of colorless solid which darkens above 300' and has an indistinct decomposition point about 353'. Since no satisfactory method could be found for recrystallization of this material, it was used directly without further purification in the next step. 4,6-Dichloronicotinonitrile(IV).-A mixture of 5.5 g. of crude 4,6-dihydroxynicotinamide, 20 g. of phosphorus pentachloride and 75 ml. of phosphorus oxychloride was heated under reflux for 3 hours. The resulting red solution was concentrated under reduced pressure to remove excess phosphorus oxychloride and the residual sirup was poured with vigorous stirring onto ice. After this aqueous mixture had stood a t 0" for 1 hour, it was extracted thoroughly with ether and the ether extracts washed with water, dried over anhydrous sodium sulfate and concentrated to give 5.23 g. of a white, crystalline solid. Sublimation of this material a t 70' (0.5 mm.) gave 4.11 g. (67%, based on 11) of pure 4,6-dichloronicotinonitrile,m.p. 134-136'. Anal. Calcd. for CeH2N2C12: C, 41.6; H , 1.2; N, 16.2. Found: C, 41.3; H, 1.2; N, 15.9. 4,6-Dimethoxynicotinonitrile(V).-Into a 1-1. 3-necked round-bottom flask, to which was attached a liquid sealed stirrer and a reflux condenser provided with a drying tube, was placed a solution of 3.0 g. of sodium in 500 ml. of absolute methanol and 7.0 g. of 4,6-dichloronicotinonitrile. The mixture was heated under reflux with stirring for 5 hours, the excess methanol was removed by distillation until solid product started to crystallize from the solution, and 250 ml. of cold water then was added. The cooled mixture was filtered and the collected solid washed with water and dried a t 100" to give 6.22 g. (94%) of colorless crystals, m.p. 153.7-155.7'. The analytical sample was prepared by recrystallization from absolute ethanol followed by sublima tion in vacuo, m.p. 154.7-155.7'. Anal. Calcd. for CsHshT202:C, 58.5; H , 4.9; N, 17.1. Found: C,58.9; H,4.9; h-,17.3. N-Methyl-3 -cyano-4-methoxy-6-pyridone (VI) .-A m iu ture of 8.2 g. of 1,6-dimetho\~-nicotinonitrileand 83 ml. of ( 5 ) J? S p a t h and I.: Tschelnitz, M o n a f s h 42, 271 (1921)
methyl iodide was heated in a sealed tube a t 130° for 5 hours and then evaporated to dryness. The crude product (8.04 g.) was recrystallized from water to give 7.65 g. (93%) of colorless needles, m.p. 241-242'. The analytical saiiiplc was prepared by sublimation a t 175' (0.5 mm.). Anal. Calcd. for C8H8X2O3:C, 58.5; H , 4.9; N,17.1. Found: C, 58.7; H, 4.9; K, 16.9. In a separate experiment, 0.1 g. of 4,6-dimethoxynicotinonitrile was heated alone in a sealed tube a t 200-223° for 10 hours, and the resulting brown solid (0.094 g., m.p. 215230') was recrystallized from water and then sublimed to give V I , identical with the material prepared as described above . 1-Methyl-4-hydroxy-Z-pyridone(VU).-The method used here was adapted from procedures reported for the hydrolysis of ricininic acid' and ricinine.5 A mixture of 2.0 g. of N niethyl-3-cyano-4-methoxy-6-pyridone and 10 nil. of concentrated hydrochloric acid in a sealed glass tube contained in :I steel pressure bomb was heated a t 150' for 4.5 hours. The cooled reaction mixture was diluted with 40 nil. of water, filtered, and the filtrate evaporated to dryness. The residue was extracted with boiling absolute ethanol, the extracts evaporated to dryness, the residue triturated with dilute ammonium hydroxide and the mixture again taken to dryness. The resulting residue again was extracted with ethanol, the extracts evaporated to dryness and the residue recrystallized from water to give a white crystalline solid which melted a t 60-70", then solidikfied and remelted After sublimation a t 150 ( 0 . 5 inin.), the a t 160-163° product melted a t 171-172". .4naZ. Calcd. for CeH71iOl: C, 57.6; H , 5.6; N, 11.2. Found: C, 57.8; H , 5.6; X, 11.2. (7) L. Maquenne and L. Philippe C n m p f ,eirii
138, ,XI6 (1904)
SOYES CHEMICAL LABORATORY
USIVERSITYO F ILLISOIS URBANA, ILLISOIS,A N D FRICKCHEMICAL LABORATORY PRINCETON UNIVERSITY SEW JERSEY PRINCETON,
Synthesis and Properties of High Specific Activity DL-a-Lipoic Acid-Si' BY RICHARD C. THOMAS A N D LESTER J. REED RECEIVED MAY13, 1955
To facilitate studies of the metabolism of the biocatalyst, a-lipoic acid, in this Laboratory, a semimicro method for the synthesis of high specific activity DL-a-lipOiC acid-S;' has been developed. The sequence of reactions employed in the synthesis is shown below. S*
1, C6H5CH2MgBr 2, H +
> CeHjCH&*H
78%
I
2, 1, KOH C&CH2S*Sa CHjCH*CH(CH2)rC02CzH5 II
Br
71%
II
Br
I11
>
I1
1, ?-a-liq. NHa 2, air, Fe3+ 1.7-8670
CH&H2CH( CH2)rCOzH
I
*S--S*
I
11.
Benzyl mercaptan-S3' was prepared by modification of the method of Wood, et aZ. The recent syn( 1 ) 1. L. Wood. J , R . Rachele,
c. RI. Stevens, 17. H
Carpenter and
